Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice

The KCNN4 potassium-ion channel has been reported to play an important role in regulating antigen-induced T cell effector functions in vitro. This study presents the first evidence that a selective KCNN4 blocker, TRAM-34, confers protection against experimental autoimmune encephalomyelitis (EAE) in the mouse model. Treatment with the KCNN4 blocker did not prevent infiltration of T cells in the spinal cord, but resulted in the reduction of both the protein and the message levels of TNF-alpha and IFN-gamma as well as the message levels of several other pro-inflammatory molecules in the spinal cord. Plasma concentrations of TRAM-34 within a 24-h period were between the in vitro IC(50) and IC(90) values for the KCNN4 channel. The effect of TRAM-34 was reversible, as indicated by the development of clinical EAE symptoms within 48 h after withdrawal of treatment. In summary, our data support the idea that KCNN4 channels play a critical role in the immune response during the development of MOG-induced EAE in C57BL/6 mice.     

Endovascular repair of traumatic thoracic aortic disruption

In a patient with multiple trauma, blunt thoracic trauma with concomitant aortic disruption is often eminently lethal, ranking second to head injury as the most common cause of trauma-related deaths. Open surgical repair of the aortic lesion has morbidity and mortality rates that are among the highest in the field of cardiovascular surgery. Results with thoracic endovascular aortic repair for traumatic aortic disruption are promising. The facility requirements, technique, and early results of thoracic endovascular aortic repair for the treatment of this difficult aortic injury are presented.     

Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs

Crohn's disease (CD) has been shown to be associated with the variants in the CARD15 gene as well as in other genes involved in the immune response. The frequencies of the variants profoundly differ among populations and so does the associated risk. We examined the associations of variants in the CARD15, TNFA and PTPN22 genes with pediatric-onset and adult-onset CD in the Czech population. Genotype, phenotype and allelic frequencies were compared between 345 patients with CD (136 pediatric-onset and 209 adult-onset patients) and 501 unrelated healthy controls. At least one minor allele of the CARD15 gene was carried by 46% patients and only 21% control subjects (OR = 3.2, 95% CI 2.4-4.4). In a multiple logistic regression model, the strongest association with CD was found for the 1007fs variant (OR = 4.6, 95% CI 3.0-7.0), followed by p.G908R (OR = 2.9, 95% CI 1.5-5.7) and p.R702W (OR = 1.7, 95% CI 1.0-2.9), while no independent association was found for the remaining variants in the CARD15 gene (p.268S, p.955I and p.289S), for the p.R620W variant in the PTPN22 gene or for the g.-308G>A variant in the TNFA gene. The age at CD onset was strongly modified by positivity for the 1007fs allele: it was present in 42% pediatric-onset and only 25% adult-onset patients. In conclusion, we report a high frequency of the minor allele of the CARD15 1007fs polymorphism in the Czech population and a strong effect of this allele on the age at disease onset.     

Uncertainties in indentation testing of articular cartilage: a fibril-reinforced poroviscoelastic study

Indentation testing provides a quantitative technique to evaluate mechanical characteristics of articular cartilage in situ and in vivo. Traditionally, analytical solutions proposed by Hayes et al. [Hayes WC, Keer LM, Herrmann G, Mockros LF. A mathematical analysis for indentation tests of articular cartilage. J Biomech 1972;5(5):541–51] have been applied for the analysis of indentation measurements, and due to their practicality, they have been used for clinical diagnostics. Using this approach, the elastic modulus is derived based on scaling factors which depend on cartilage thickness, indenter radius and Poisson's ratio, and the cartilage model is assumed isotropic and homogeneous, thereby greatly simplifying the true tissue characteristics. The aim was to investigate the validity of previous model assumptions for indentation testing. Fibril-reinforced poroviscoelastic cartilage (FRPVE) model including realistic tissue characteristics was used to simulate indentation tests. The effects of cartilage inhomogeneity, anisotropy, and indentation velocity on the indentation response were evaluated, and scaling factors from the FRPVE analysis were derived. Subsequently, the validity of scaling factors obtained using the traditional and the FRPVE analyses was studied by calculating indentation moduli for bovine cartilage samples, and comparing these values to those obtained experimentally in unconfined compression testing. Collagen architecture and compression velocity had significant effects on the indentation response. Isotropic elastic analysis gave significantly higher (30–107%) Young's moduli for indentation compared to unconfined compression testing. Modification of Hayes’ scaling factors by accounting for cartilage inhomogeneity and anisotropy improved the agreement of Young's moduli obtained for the two test configurations by 14–28%. These results emphasize the importance of realistic cartilage structure and mechanical properties in the indentation analysis. Although it is not possible to fully describe tissue inhomogeneity and anisotropy with just the Young's modulus and Poisson's ratio, accounting for inhomogeneity and anisotropy in these two parameters may help to improve the in vivo characterization of tissue using arthroscopic indentation testing.     

Mercury-induced cognitive impairment in metallothionein-1/2 null mice

Metallothioneins are central for the metabolism and detoxification of transition metals. Exposure to mercury during early neurodevelopment is associated with neurocognitive impairment. Given the importance of metallothioneins in mercury detoxification, metallothioneins may be a protective factor against mercury-induced neurocognitive impairment. Deletion of the murine metallothionein-1 and metallothionein-2 genes causes choice accuracy impairments in the 8-arm radial maze. We hypothesize that deletions of metallothioneins genes will make metallothionein-null mice more vulnerable to mercury-induced cognitive impairment. We tested this hypothesis by exposing MT1/MT2-null and wild-type mice to developmental mercury (HgCl₂) and evaluated the resultant effects on cognitive performance on the 8-arm radial maze. During the early phase of learning metallothionein-null mice were more susceptible to mercury-induced impairment compared to wildtype mice. Neurochemical analysis of the frontal cortex revealed that serotonin levels were higher in metallothionein-null mice compared to wild-type mice. This effect was independent of mercury exposure. However, dopamine levels in mercury-exposed metallothionein-null mice were lower compared to mercury-exposed wild-type mice. This work shows that deleting metallothioneins increase the vulnerability to developmental mercury-induced neurocognitive impairment. Metallothionein effects on monoamine transmitters may be related to this cognitive effect.     

Alternative Stimulation Intensities for Mapping Cortical Motor Area with Navigated TMS

Navigated transcranial magnetic stimulation (nTMS) is becoming a popular tool in pre-operative mapping of functional motor areas. The stimulation intensities used in the mapping are commonly suprathreshold intensities with respect to the patient’s resting motor threshold (rMT). There is no consensus on which suprathreshold intensity should be used nor on the optimal criteria for selecting the appropriate stimulation intensity (SI). In this study, the left motor cortices of 12 right-handed volunteers (8 males, age 24–61 years) were mapped using motor evoked potentials with an SI of 110 and 120 % of rMT and with an upper threshold (UT) estimated by the Mills–Nithi algorithm. The UT was significantly lower than 120 % of rMT (p < 0.001), while no significant difference was observed between UT and 110 % of rMT (p = 0.112). The representation sizes followed a similar trend, i.e. areas computed based on UT (5.9 cm²) and 110 % of rMT (5.0 cm²) being smaller than that of 120 % of rMT (8.8 cm²) (p ≤ 0.001). There was no difference in representation sizes between 110 % of rMT and UT. The variance in representation size was found to be significantly lower with UT compared to 120 % of rMT (p = 0.048, uncorrected), while there was no difference between 110 % of rMT and UT or 120 % of rMT. Indications of lowest inter-individual variation in representation size were observed with UT; this is possibly due to the fact that it takes into account the individual input–output characteristics of the motor cortex. Therefore, the UT seems to be a good option for SI in motor mapping applications to outline functional motor areas with nTMS and it could potentially reduce the inter-individual variation caused by the selection of SI in motor mapping in pre-surgical applications and radiosurgery planning.